ABSTRACT: Bone is a primary site of metastasis from prostate cancer (PCa). More than 80% of patients with recurrent PCa suffer from metastatic bone lesions, and there are currently no available treatments that can significantly improve patient outcomes. In order to identify effective therapeutic targets for this devastating and incurable disease, we need to understand the molecular mechanisms that drive tumor cell adaptation, progression and survival in the bone marrow niche. Age and obesity are significant risk factors for development of bone metastatic lesions. In fact, obese and overweight men with PCa are three times more likely to develop metastatic disease compared to normal- weight men with same treatment regimen. The mechanisms behind this association are currently not understood. Both age and obesity greatly increase numbers fat cells (adipocytes) in the bone marrow. Fat cells negatively affect bone metabolism and function, and escalate bone degradation making the bone marrow more supportive of tumor growth. Data from our lab demonstrate that PCa tumors grow larger and progress faster in mice with increased marrow adiposity due to high fat diet. Tumor cells interacting with adipocytes are more invasive and have high expression of protein involved in fat metabolism and transport (i.e., Fatty Acid Binding Protein 4; FABP4) and proinflammatory cytokine IL-1. We hypothesize that bone marrow adipocytes promote and support progression of metastatic PCa in bone through the FABP4/IL-1-dependent mechanisms. We propose a multi-faceted approach that includes multiple independent mouse models of marrow adiposity, models of intraosseous tumor growth, novel cell culture techniques, pharmacological and genetic manipulation, and lipidomic technology to uncover functional role of bone marrow fat cells in PCa progression in skeleton. We will perform these studies in three Aims. We will: 1) Establish the significance of marrow adipocytes in growth and progression of PCa cells in bone using independent models of marrow adiposity and bone metastasis samples from PCa patients; 2) Elucidate the mechanism of FABP4/IL-1 involvement in PCa progression in bone by genetic and biochemical manipulation of fatty acid mobilization and FABP4 expression in vitro and in vivo; and 3) Define the effects of marrow adiposity on fatty acyl lipidome of metastatic tumor cells using lipidomics technology to identify lipid mediators that lead to invasive behavior in tumor cells. Together, our findings will provide functional evidence for involvement of bone marrow fat cells in supporting growth, adaptation and progression of metastatic PCa cells in bone via FABP4/IL-1 axis. This work will unravel novel candidate therapeutic targets to provide improvement in patient outcomes. Findings of this work are likely to have high relevance beyond PCa and extend to other bone-trophic cancers.